Glioblastoma is one of the deadliest forms of brain cancer. All glioblastomas contain fast-growing and aggressive tumor cells. The current standard of care, temozolomide (TMZ), extends patient’s lives by a median of 7 months; however, this chemotherapy only works for a subset of patients, and many of those patients rapidly acquire resistance to this treatment. Additional, more efficacious treatments are direly needed for glioblastoma patients.

Dr. Jarvis Hill’s postdoctoral research in Dr. Seth Herzon’s lab at Yale University aims to enable the next generation of glioblastoma therapies. The Herzon lab recently identified a novel small molecule, KL-50, that is effective against glioblastomas lacking the O6-methylguanine-DNA-methyltransferase (MGMT). However, this small molecule does not work on MGMT-positive glioblastomas. In this research, Dr. Hill will develop tumor-specific MGMT inhibitors that can be combined with KL-50 to treat patients with MGMT-positive glioblastoma.

Part of Dr. Hill’s interest in brain tumors grew out of his Ph.D. research in Dr. David Crich’s lab at the University of Georgia. As an organic chemist, Hill devised a novel synthesis for trisubstituted hydroxylamines. Recognizing that these are underrepresented functional groups in medicinal chemistry, Hill next evaluated the drug-like properties of molecules where he replaced hydrocarbons, ethers, or amines with a trisubstituted hydroxylamine. In contrast with long-standing expectations, Hill found that these substitutions were stable and generally well tolerated. Then, Hill used the trisubstituted hydroxylamine motif as a key structural unit to develop an epidermal growth factor receptor (EGFR) inhibitor with excellent brain penetration, which may be useful for treating brain metastases driven by aberrant EGFR. Now, Dr. Hill will turn his dual focus on synthetic medicinal chemistry and neuro-oncology towards finding glioblastoma therapeutics during his postdoctoral research.